Introduction: For the past decade, treatment options for acute myeloid leukemia (AML) have evolved with the approval of hypomethylating agents and the BCL-2 inhibitor venetoclax in late 2018. Historically, older patients (≥60 years) and those with comorbid conditions, who were poor candidates for intensive chemotherapy (IC), were offered less effective non-intensive (NI) treatments or no disease-specific therapy at all. This changed with the advent of combining hypomethylating agents with venetoclax-based NI treatment regimens, which significantly improved outcomes in patients who were previously unable to receive IC. There is limited population-level data on outcome measures from community practices in this new era of AML therapy; thus, we conducted this retrospective cohort study to evaluate the impact of evolving AML treatment practices on overall survival in a real-world setting.

Methods: The study cohort included 1,511 adults diagnosed with AML from January 1, 2015, to December 31, 2024, within Kaiser Permanente Northern California (median age 71 years, 45% female, 61% White, 75% with any comorbid condition and 36% with moderate to severe comorbidities based on Charlson comorbidity index). Therapeutic regimens were categorized into three groups based on clinical practice guidelines: IC, NI therapy, and no leukemia-directed treatment at all. Survival outcomes were evaluated using the Kaplan-Meier method and log-rank tests. Cox proportional hazards regression analyses were used to evaluate covariate effects on survival.

Results: Comparing treatment regimens across biennial periods, the use of NI therapies more than doubled from 23% of patients diagnosed in 2015-2016 to 56% in 2023-2024 (p<0.0001), while IC use decreased from 41% to 28% (p<0.0001). The proportion of untreated patients after initial diagnoses was reduced by half over the same period, from 36% to 16% (p<0.0001). The utilization of allogeneic bone marrow transplants (BMT) increased from 15% in 2015-2016 to 27% in 2023-2024 (p=0.001). This coincided with better survival, as one-year survival rates increased from 30% for patients diagnosed in 2015-2016 to 55% for those diagnosed in 2023-2024 (p<0.0001).

Multivariate regression revealed that older age and a higher Charlson comorbidity index predicted the receipt of NI therapy, as did diagnosis years from 2019 or later. Unadjusted five-year overall survival was significantly different between treatment groups: 43% for patients receiving any IC, versus 10% for those receiving NI therapy alone (p<0.0001). However, this survival gap narrowed significantly for patients who proceeded to BMT, with comparable five-year survival rates of 59% after IC followed by BMT, and 46% after NI therapy followed by BMT (p<0.0001). This was further supported by the multivariate proportional hazards regression: when controlling for other variables (diagnosis year, age, sex, race and ethnicity, Charlson comorbidity index, and BMT status), the hazard ratio for NI versus IC treatment was not statistically significant (p=0.35). However, patients receiving a BMT had significantly better survival than those who did not (HR=0.59, 95% CI: 0.46-0.75).

Conclusion: This population-based study demonstrates that the adoption of hypomethylating agents in combination with venetoclax-based NI therapies has successfully expanded treatment to a greater proportion of patients diagnosed with AML, particularly to include older individuals and those with significant comorbid conditions, patients who may have previously gone untreated. This shift in treatment paradigms has led to an improvement in overall survival. While unadjusted survival is superior with IC, this difference is largely mitigated by subsequent BMT, a key determinant of long-term success. Patients bridged to BMT following NI therapy achieved five-year survival rates comparable to those who received IC before BMT. These results reflecting community based real-world data within a large integrated healthcare system underscore a major advancement in AML care, establishing NI therapy as an effective bridge to curative-intent transplantation and as a promising pathway to long-term survival for a broader patient population.

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2025
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